NM_000249.4(MLH1):c.677G>T (p.Arg226Leu) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 28, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000709741.3

Allele description [Variation Report for NM_000249.4(MLH1):c.677G>T (p.Arg226Leu)]

NM_000249.4(MLH1):c.677G>T (p.Arg226Leu)

Gene:

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000249.4(MLH1):c.677G>T (p.Arg226Leu)

Other names:

p.R226L:CGA>CTA

HGVS:

NC_000003.12:g.37012099G>T
NG_007109.2:g.23750G>T
NM_000249.4:c.677G>TMANE SELECT
NM_001167617.3:c.383G>T
NM_001167618.3:c.-47G>T
NM_001167619.3:c.-47G>T
NM_001258271.2:c.677G>T
NM_001258273.2:c.-47G>T
NM_001258274.3:c.-47G>T
NM_001354615.2:c.-47G>T
NM_001354616.2:c.-47G>T
NM_001354617.2:c.-47G>T
NM_001354618.2:c.-47G>T
NM_001354619.2:c.-47G>T
NM_001354620.2:c.383G>T
NM_001354621.2:c.-140G>T
NM_001354622.2:c.-253G>T
NM_001354623.2:c.-253G>T
NM_001354624.2:c.-150G>T
NM_001354625.2:c.-150G>T
NM_001354626.2:c.-150G>T
NM_001354627.2:c.-150G>T
NM_001354628.2:c.677G>T
NM_001354629.2:c.578G>T
NM_001354630.2:c.677G>T
NP_000240.1:p.Arg226Leu
NP_000240.1:p.Arg226Leu
NP_001161089.1:p.Arg128Leu
NP_001245200.1:p.Arg226Leu
NP_001341549.1:p.Arg128Leu
NP_001341557.1:p.Arg226Leu
NP_001341558.1:p.Arg193Leu
NP_001341559.1:p.Arg226Leu
LRG_216t1:c.677G>T
LRG_216:g.23750G>T
LRG_216p1:p.Arg226Leu
NC_000003.11:g.37053590G>T
NM_000249.3:c.677G>T
P40692:p.Arg226Leu

Protein change:

R128L

Links:

UniProtKB: P40692#VAR_004451; dbSNP: rs63751711

NCBI 1000 Genomes Browser:

rs63751711

Molecular consequence:

NM_001167618.3:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-47G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-140G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-253G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-253G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-150G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.383G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.383G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.578G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.677G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:: COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000840010	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 27, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004193067	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 28, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000840010

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 27, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004193067

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 28, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840010.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

A heterozygous c. 677G>T (p.Arg226Leu) pathogenic variant in the MLH1 gene was detected in this individual. This variant has been previously described as disease-causing (PMID: 18383312, 16830052, 8566964, 12655568). Therefore, we consider this variant to be likely pathogenic. [alaimo, 2018-01-24]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004193067.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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